Project Summary Whole exome and whole genome sequencing (WGS) have expanded our ability to determine the genetic etiology of previously undiagnosed disorders. We propose a multicenter prospective cohort study to evaluate the emerging technology of WGS for the management of fetuses with structural anomalies. We hypothesize that a significant subset of fetal structural anomalies has a genetic etiology identifiable by whole genome sequencing (WGS) and that prenatal knowledge of this information will improve perinatal care, reduce unnecessary diagnostic testing, reduce the cost of care, and improve quality of life for both the child and the family. Our aims are to investigate these multiple aspects of prenatal sequencing in a single study with an innovative integrated prospective design, which will permit a robust evaluation of the benefits and risks of delivering diagnostic and prognostic genetic testing results in a prenatal setting. To certify sufficient funds to accomplish all goals, we have secured significant industry support for the cost of WGS. The study will determine, in a sequential population of women with pregnancies with unselected fetal structural anomalies, the frequency of pathogenic, likely pathogenic, and uncertain genomic variants identifiable by WGS. To determine the impact of this information on clinical care we will prospectively recruit a control population of women with unsequenced pregnancies with similar structural anomalies and follow the infants from both cohorts up to 1 year of age. This study component will evaluate differences in healthcare management and cost. The educational, counseling and psychosocial impact of WGS data during the prenatal period, in the nursery and through 1 year of life will also be evaluated. Since the analytical and clinical tools needed for the full translation of WGS into care are still developing, we will investigate and optimize bioinformatic tools to improve identification of pathogenic and likely pathogenic mutations associated with prenatal phenotypes of established disease genes, as well as identification of new genes associated with presently undiagnosed fetal/neonatal phenotypes. Accomplishing the aims that address our study hypotheses will require the establishment of a tightly integrated team with collective expertise in diagnosis of fetal anomalies, interpretation of WGS data, clinical genetics, cost effectiveness analysis, and ethical, legal and psychosocial outcomes. The assembled team has expertise in each of these areas as well as a track record of prior productive collaboration. This study will provide an in-depth evaluation of the prenatal diagnostic value of WGS prior to its responsible introduction into practice and will provide independent data to guide its translation.